The goal of this proposal is to develop a drug that will be therapeutic for obesity and diabetes and improve exercise tolerance. Obesity, diabetes and exercise are inextricably linked such that an agent that improves exercise tolerance or prevents obesity or the development of diabetes will likely have a therapeutic role in all three conditions. Obesity is a global epidemic, which promotes diabetes and is a major cardiovascular risk factor, resulting in reduced life expectancy. Obesity and diabetes can be caused by dietary, behavioral and genetic factors. Both diseases are a public health problem and finding a novel therapeutic approach would be a major advance. Recently, we reported a novel, genetically engineered mouse model, where the adenylyl cyclase (AC) type 5 isoform is knocked out (AC5 KO). AC5 inactivation resulted in increased longevity and was protective against stress. Furthermore, the AC5 KO mice ate more than WT mice, but weighed less, suggesting that AC5 inhibition could be a novel approach to weight loss. The AC5 KO mouse also demonstrates enhanced exercise tolerance. Concurrently, we have developed a pharmacological AC5 inhibitor which also protects against cardiovascular stress. The main hypothesis of this pilot project is that inhibition of AC5 in mice protects against obesity. Our three working hypotheses are: A. Inhibition of AC5 will reduce obesity in mice fed a high fat diet, and B. Inhibition of AC5 will protect against the development of insulin resistance and diabetes, and C. Inhibition of AC5 will improve exercise tolerance in those mice. In view of the significance of obesity and diabetes in the US population, there is a major health benefit to this project. PUBLIC HEALTH RELEVANCE: Obesity is a global epidemic, which promotes diabetes and is a major cardiovascular risk factor, resulting in reduced life expectancy. Obesity and diabetes can be caused by dietary, behavioral and genetic factors;several genes have been identified to be involved in the development of obesity. Both diseases are a public health problem and finding a novel therapeutic approach would be a major advance.